Dosing strategies for switching from oral risperidone to paliperidone palmitate: Effects on clinical outcomes.

IntroductionThere are currently no guidelines for switching patients from oral risperidone to paliperidone palmitate (Invega Sustenna®). Furthermore, the paliperidone long-acting injectable (LAI) package insert does not recommend bridging with oral antipsychotics, which may result in inadequate serum concentrations in patients on ≥4 mg/d risperidone.MethodsThis study evaluated the effects of suboptimal dosing and bridging in patients switched from oral risperidone to paliperidone LAI on hospitalization days, emergency department (ED)/mental health urgent care visits, and no-shows/cancellations to mental health appointments. Patients were categorized into optimal or suboptimal dosing based on their loading and maintenance paliperidone doses. Patients on risperidone ≥4 mg/d were categorized as bridged if they received risperidone for ≥7 days after the first paliperidone injection.ResultsThere were no significant differences in outcomes between optimally and suboptimally dosed patients. There were statistically significant reductions in hospitalization days in patients who were bridged compared with patients who were not bridged. There were statistically significant reductions in hospitalization days and ED/mental health urgent care visits after switching to paliperidone LAI.DiscussionThe results of this study indicate that bridging patients who are on ≥4 mg/d risperidone, when converting to paliperidone LAI, is associated with reductions in hospitalization days. However, more research is required to determine the optimal dose and duration of the bridge. The results also indicate that switching patients from oral risperidone to paliperidone LAI, even if the dose is suboptimal, is associated with reductions in hospitalization days and ED/mental health urgent care visits

Phase-Controlled Force and Magnetization Oscillations in Superconducting Ballistic Nanowires

The emergence of superconductivity-induced phase-controlled forces in the (0.01-0.1) nN range, and of magnetization oscillations, in nanowire junctions, is discussed. A giant magnetic response to applied weak magnetic fields, is predicted in the ballistic Josephson junction formed by a superconducting tip and a surface, bridged by a normal metal nanowire where Andreev states form.Comment: 5 pages, 3 figure

A functional variant in the serotonin receptor 7 gene (HTR7), rs7905446, is associated with good response to SSRIs in bipolar and unipolar depression.

Predicting antidepressant response has been a clinical challenge for mood disorder. Although several genome-wide association studies have suggested a number of genetic variants to be associated with antidepressant response, the sample sizes are small and the results are difficult to replicate. Previous animal studies have shown that knockout of the serotonin receptor 7 gene (HTR7) resulted in an antidepressant-like phenotype, suggesting it was important to antidepressant action. In this report, in the first stage, we used a cost-effective pooled-sequencing strategy to sequence the entire HTR7 gene and its regulatory regions to investigate the association of common variants in HTR7 and clinical response to four selective serotonin reuptake inhibitors (SSRIs: citalopram, paroxetine, fluoxetine and sertraline) in a retrospective cohort mainly consisting of subjects with bipolar disorder (n = 359). We found 80 single-nucleotide polymorphisms (SNPs) with false discovery rate < 0.05 associated with response to paroxetine. Among the significant SNPs, rs7905446 (T/G), which is located at the promoter region, also showed nominal significance (P < 0.05) in fluoxetine group. GG/TG genotypes for rs7905446 and female gender were associated with better response to two SSRIs (paroxetine and fluoxetine). In the second stage, we replicated this association in two independent prospective samples of SSRI-treated patients with major depressive disorder: the MARS (n = 253, P = 0.0169) and GENDEP studies (n = 432, P = 0.008). The GG/TG genotypes were consistently associated with response in all three samples. Functional study of rs7905446 showed greater activity of the G allele in regulating expression of HTR7. The G allele displayed higher luciferase activity in two neuronal-related cell lines, and estrogen treatment decreased the activity of only the G allele. Electrophoretic mobility shift assay suggested that the G allele interacted with CCAAT/enhancer-binding protein beta transcription factor (TF), while the T allele did not show any interaction with any TFs. Our results provided novel pharmacogenomic evidence to support the role of HTR7 in association with antidepressant response

On the Origin of Asymmetries in Bilateral Supernova Remnants

AIMS: We investigate whether the morphology of bilateral supernova remnants (BSNRs) observed in the radio band is determined mainly either by a non-uniform interstellar medium (ISM) or by a non-uniform ambient magnetic field. METHODS: We perform 3-D MHD simulations of a spherical SNR shock propagating through a magnetized ISM. Two cases of shock propagation are considered: 1) through a gradient of ambient density with a uniform ambient magnetic field; 2) through a homogeneous medium with a gradient of ambient magnetic field strength. From the simulations, we synthesize the synchrotron radio emission, making different assumptions about the details of acceleration and injection of relativistic electrons. RESULTS: We find that asymmetric BSNRs are produced if the line-of-sight is not aligned with the gradient of ambient plasma density or with the gradient of ambient magnetic field strength. We derive useful parameters to quantify the degree of asymmetry of the remnants that may provide a powerful diagnostic of the microphysics of strong shock waves through the comparison between models and observations. CONCLUSIONS: BSNRs with two radio limbs of different brightness can be explained if a gradient of ambient density or, most likely, of ambient magnetic field strength is perpendicular to the radio limbs. BSNRs with converging similar radio arcs can be explained if the gradient runs between the two arcs.Comment: 14 pages, 8 Figures; paper accepted for publication in A&A; the paper with high-resolution figures can be downloaded at http://www.astropa.unipa.it/~orlando/PAPERS/sorlando_6045.pd

Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2D6 and CYP2C19 Genotypes and Dosing of Selective Serotonin Reuptake Inhibitors

Selective serotonin reuptake inhibitors (SSRIs) are primary treatment options for major depressive and anxiety disorders. CYP2D6 and CYP2C19 polymorphisms can influence the metabolism of SSRIs, thereby affecting drug efficacy and safety. We summarize evidence from the published literature supporting these associations and provide dosing recommendations for fluvoxamine, paroxetine, citalopram, escitalopram, and sertraline based on CYP2D6 and/or CYP2C19 genotype (updates at www.pharmgkb.org)

Ligand-Receptor Interactions

The formation and dissociation of specific noncovalent interactions between a variety of macromolecules play a crucial role in the function of biological systems. During the last few years, three main lines of research led to a dramatic improvement of our understanding of these important phenomena. First, combination of genetic engineering and X ray cristallography made available a simultaneous knowledg of the precise structure and affinity of series or related ligand-receptor systems differing by a few well-defined atoms. Second, improvement of computer power and simulation techniques allowed extended exploration of the interaction of realistic macromolecules. Third, simultaneous development of a variety of techniques based on atomic force microscopy, hydrodynamic flow, biomembrane probes, optical tweezers, magnetic fields or flexible transducers yielded direct experimental information of the behavior of single ligand receptor bonds. At the same time, investigation of well defined cellular models raised the interest of biologists to the kinetic and mechanical properties of cell membrane receptors. The aim of this review is to give a description of these advances that benefitted from a largely multidisciplinar approach

Towards the clinical implementation of pharmacogenetics in bipolar disorder.

BackgroundBipolar disorder (BD) is a psychiatric illness defined by pathological alterations between the mood states of mania and depression, causing disability, imposing healthcare costs and elevating the risk of suicide. Although effective treatments for BD exist, variability in outcomes leads to a large number of treatment failures, typically followed by a trial and error process of medication switches that can take years. Pharmacogenetic testing (PGT), by tailoring drug choice to an individual, may personalize and expedite treatment so as to identify more rapidly medications well suited to individual BD patients.DiscussionA number of associations have been made in BD between medication response phenotypes and specific genetic markers. However, to date clinical adoption of PGT has been limited, often citing questions that must be answered before it can be widely utilized. These include: What are the requirements of supporting evidence? How large is a clinically relevant effect? What degree of specificity and sensitivity are required? Does a given marker influence decision making and have clinical utility? In many cases, the answers to these questions remain unknown, and ultimately, the question of whether PGT is valid and useful must be determined empirically. Towards this aim, we have reviewed the literature and selected drug-genotype associations with the strongest evidence for utility in BD.SummaryBased upon these findings, we propose a preliminary panel for use in PGT, and a method by which the results of a PGT panel can be integrated for clinical interpretation. Finally, we argue that based on the sufficiency of accumulated evidence, PGT implementation studies are now warranted. We propose and discuss the design for a randomized clinical trial to test the use of PGT in the treatment of BD

THE ANALYSIS OF PUNCTUATION USE IN UNPUNCTUATED PASSAGES: A DISCOURSE-GRAPHOLOGY PERSPECTIVE

Diski Eginda Rismianti. 14111310149. The Analysis of Punctuation Use in Unpunctuated Passages: A Discourse-Graphology Perspective. Punctuation is the basic element in writing which is important to clarify meaning. Without punctuation or ignoring the rule of punctuation in a passage, the writing will be ambiguous. The writing course in IAIN Syekh Nurjati Cirebon is studied by English Student in 5 levels. Based the phenomenon, this research aims to find out the students’ error in the use of punctuation and how does the use relate to the meaning of restrictive and nonrestrictive elements. The analyses process in this research is constructed based on the theory from Marcella Frank. This research used qualitative method in analyzing data where the data contains the two original passages which is taken from the book of academic writing and the three participants’ work which are got by examining the passages as a main data source to be analyzed in this research. Those passages are changed be unpunctuated passages then examined to the 3 EFL learner which comes from the high score, medium score, and low score of writing. The result of this analysis shows that there are fifteen punctuation marks which are used in the two passages; they are capitalization, periods, commas, semicolons, colons, quotation marks, parentheses, apostrophes, hyphen, en dashes, ellipses, percent, underscore, at sign, and citation. FP has highest number of error in Capitalization with 100%. SP has big problem in commas exactly in the nineteenth rule with 90% and TP are wrong in parentheses. For restrictive and nonrestrictive elements, restrictive elements has higher number than nonrestrictive elements, except is in appositive. The numbers of the elements are same with the three participants. The differences come from the number of appositive which passages has higher number of nonrestrictive appositive than restrictive appositives. The results show that punctuation in unpunctuated passages used the rule from APA (American Psychological Association). The effects of the use of punctuation are in the number of sentences and clauses, types of phrases, and restrictive and nonrestrictive elements. For the students’ error, there are some sentences in FP and TP which only contain phrase. Key words: Punctuation Marks, Restrictive and Nonrestrictive Clause, Restrictive and Nonrestrictive Phrase, Restrictive and Nonrestrictive Appositives